Use

ABSTRACT

The present invention relates to a new use of oxindole derivatives of formula I, as a free base or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the prevention and/or treatment of dementia related diseases, Alzheimer&#39;s Disease and conditions associated with glycogen synthase kinase-3. Formula (I) wherein R 1 , R 2 , R 3 , ring Z, m and n are as defined as in claim  1 . The present invention further relates to a method of prevention and/or treatment of dementia related diseases, Alzheimer&#39;s Disease and conditions associated with glycogen synthase kinase-3, as well as a pharmaceutical composition for said use.

FIELD OF INVENTION

The present invention relates to a new use of oxindole derivatives, as afree base or pharmaceutically acceptable salts thereof, in themanufacture of a medicament for the treatment and/or prevention ofdementia related diseases, Alzheimer's Disease and conditions associatedwith glycogen synthase kinase-3. The present invention further relatesto a method of treatment and/or prevention of dementia related diseases,Alzheimer's Disease and conditions associated with glycogen synthasekinase-3.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinasecomposed of two isoforms (α and β), which are encoded by distinct genesbut are highly homologous within the catalytic domain. GSK3 is highlyexpressed in the central and peripheral nervous system. GSK3phosphorylates several substrates including tau, β-catenin, glycogensynthase, pyruvate dehydrogenase and elongation initiation factor 2b(eIF2b). Insulin and growth factors activate protein kinase B, whichphosphorylates GSK3 on the serine 9 residue and inactivates it.

Alzheimer's Disease (AD) Dementias, and Taupathies.

AD is characterized by cognitive decline, cholinergic dysfunction andneuronal death, neurofibrillary tangles and senile plaques consisting ofamyloid-β deposits. The sequence of these events in AD is unclear, butbelieved to be related. Glycogen synthase kinase 3β (GSK3β) or Tau (τ)phosphorylating kinase selectively phosphorylates the microtubuleassociated protein τ in neurons at sites that are hyperphosphorylated inAD brains. Hyperphosphorylated protein τ has lower affinity formicrotubules and accumulates as paired helical filaments, which are themain components that constitute neurofibrillary tangles and neuropilthreads in AD brains. This results in depolymerization of microtubules,which leads to dying back of axons and neuritic dystrophy.Neurofibrillary tangles are consistently found in diseases such as AD,amyotrophic lateral sclerosis, parkinsonism-dementia complex of Gaum,corticobasal degeneration, dementia pugilistica and head trauma, Down'ssyndrome, postencephalatic parkinsonism, progressive supranuclear palsy,Niemann-Pick's Disease and Pick's Disease. Addition of amyloid-β toprimary hippocampal cultures results in hyperphosphorylation of t and apaired helical filaments-like state via induction of GSK3β activity,followed by disruption of axonal transport and neuronal death (Imahoriand Uchida., J. Biochem 121:179-188, 1997). GSK3β preferentially labelsneurofibrillary tangles and has been shown to be active in pre-tangleneurons in AD brains. GSK3 protein levels are also increased by 50% inbrain tissue from AD patients. Furthermore, GSK3β phosphorylatespyruvate dehydrogenase, a key enzyme in the glycolytic pathway andprevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS93:2719-2723, 1996). Acetyl-Co-A is critical for the synthesis ofacetylcholine, a neurotransmitter with cognitive functions. Thus, GSK3βinhibition may have beneficial effects in progression as well as thecognitive deficits associated with Alzheimer's disease and otherabove-referred to diseases.

Chronic and Acute Neurodegenerative Diseases.

Growth factor mediated activation of the PI3K/Akt pathway has been shownto play a key role in neuronal survival. The activation of this pathwayresults in GSK3, inhibition. Recent studies (Bhat et. al., PNAS97:11074-11079 (2000)) indicate that GSK3, activity is increased incellular and animal models of neurodegeneration such as cerebralischemia or after growth factor deprivation. For example, the activesite phosphorylation was increased in neurons vulnerable to apoptosis, atype of cell death commonly thought to occur in chronic and acutedegenerative diseases such as Alzheimer's Disease, Parkinson's Disease,amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia,ischemic stroke and head trauma. Lithium was neuroprotective ininhibiting apoptosis in cells and in the brain at doses that resulted inthe inhibition of GSK3β. Thus GSK3β inhibitors could be useful inattenuating the course of neurodegenerative diseases.

Bipolar Disorders (BD)

Bipolar Disorders are characterised by manic episodes and depressiveepisodes. Lithium has been used to treat BD based on its moodstabilising effects. The disadvantage of lithium is the narrowtherapeutic window and the danger of overdosing that can lead to lithiumintoxication. The recent discovery that lithium inhibits GSK3 attherapeutic concentrations has raised the possibility that this enzymerepresents a key target of lithium's action in the brain (Stambolic etal., Curr. Biol. 6:1664-1668, 1996; Klein and Melton; PNAS 93:8455-8459,1996). Inhibition of GSK30 may therefore be of therapeutic relevance inthe treatment of BD as well as in AD patients that have affectivedisorders.

Schizophrenia

GSK3 is involved in signal transduction cascades of multiple cellularprocesses, particularly during neural development. Kozlovsky et al (Am JPsychiatry 2000 May;157(5):831-3) found that GSK3β levels were 41% lowerin the schizophrenic patients than in comparison subjects. This studyindicates that schizophrenia involves neurodevelopmental pathology andthat abnormal GSK3 regulation could play a role in schizophrenia.Furthermore, reduced β-catenin levels have been reported in patientsexhibiting schizophrenia (Cotter et al., Neuroreport 9:1379-1383(1998)).

Diabetes

Insulin stimulates glycogen synthesis in skeletal muscles via thedephosphorylation and thus activation of glycogen synthase. Underresting conditions, GSK3 phosphorylates and inactivates glycogensynthase via dephosphorylation. GSK3 is also over-expressed in musclesfrom Type II diabetic patients (Nikoulina et al., Diabetes 2000February;49(2):263-71). Inhibition of GSK3 increases the activity ofglycogen synthase thereby decreasing glucose levels by its conversion toglycogen. GSK3 inhibition may therefore be of therapeutic relevance inthe treatment of Type I and Type II diabetes and diabetic neuropathy.

Hair Loss

GSK3 phosphorylates and degrades β-catenin. O-catenin is an effector ofthe pathway for keratonin synthesis. β-catenin stabilisation may be leadto increase hair development. Mice expressing a stabilised β-catenin bymutation of sites phosphorylated by GSK3 undergo a process resembling denovo hair morphogenesis (Gat et al., Cell 1998 Nov. 25;95 (5):605-14)).The new follicles formed sebaceous glands and dermal papilla, normallyestablished only in embryogenesis. Thus GSK3 inhibition may offertreatment for baldness.

Oral Contraceptives

Vijajaraghavan et al. (Biol Reprod 2000 June; 62 (6):1647-54) reportedthat GSK3 is high in motile versus immotile sperm. Immunocytochemistryrevealed that GSK3 is present in the flagellum and the anterior portionof the sperm head. These data suggest that GSK3 could be a key elementunderlying motility initiation in the epididymis and regulation ofmature sperm function. Inhibitors of GSK3 could be useful ascontraceptives for males.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of general formula I are disclosed in WO 99/10349. The effectof the compounds on reducing antiangiogenic and/or vascular permeabilityin mammals has been investigated.

It has now suprisingly been found that the group of oxindole derivativesas decribed in WO 99/10349 are well suited for inhibiting glycogensynthase kinase-3. Said glycogen synthase kinase-3 inhibitors aresuitable in the prevention and/or treatment of conditions associatedwith glycogen synthase kinase-3 in the central and peripheral nervoussystem. In particular, the compounds of the invention are expected to besuitable for prevention and/or treatment of especially dementia relateddiseases and Alzheimer's Disease.

The dementia related diseases are selected from the group consisting ofFrontotemporal dementia Parkinson's Type, Parkinson dementia complex ofGuam, HIV dementia, diseases with associated neurofibrillar tanglepathologies, predemented states, vascular dementia, dementia with Lewybodies, Frontotemporal dementia and dementia pugilistica. The compoundsof the invention are also expected to be suitable for prevention and/ortreatment of amyotrophic lateral sclerosis, corticobasal degeneration,Down syndrome, Huntington's Disease, Parkinson's Disease,postencephelatic parkinsonism, progressive supranuclear palsy, Pick'sDisease, Niemann-Pick's Disease, stroke, head trauma and other chronicneurodegenerative diseases, Bipolar Disease, affective disorders,depression, schizophrenia, cognitive disorders, hair loss andcontraceptive medication.

The compounds of the invention are further expected to be suitable forprevention and/or treatment of Mild Cognitive Impairment, Age-AssociatedMemory Impairment, Age-Related Cognitive Decline, Cognitive ImpairementNo Dementia, mild cognitive decline, mild neurocognitive decline,Late-Life Forgetfulness, memory impairment and cognitive impairment andandrogenetic alopecia.

In the present invention GSK3 inhibitors of general formula I may beused in the manufacturing of a medicament for the treatment and/orprevention of conditions associated with glycogen synthase kinase-3:

wherein:

-   ring Z is a 5 or 6 membered heterocyclic ring containing 1 to 3    heteroatoms selected independently from O, N and S but not more than    2 nitrogen atom;-   R¹ is hydrogen or C₁₋₃alkyl;-   R² is hydroxy, halogeno, fluoromethyl, difluoromethyl,    trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,    2,2,2-trifluoroethyl, cyano, amino, nitro, C₁₋₃alkyl, C₁₋₃alkoxy,    C₁₋₃alkanoyloxy, C₂₋₄alkanoyl, C₁₋₄alkanoylamino,    C₁₋₄alkoxycarbonyl, C₁₋₄alkylthio, C₁₋₄alkylsulphinyl,    C₁₋₄alkylsulphonyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,    N,N-di(C₄alkyl)carbamoyl, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl,    N,N-di(C₁₋₄alkyl)aminosulphonyl or C₁₋₄alkylsulphonylamino, or-   R² is selected from one of the following groups:    -   1) R⁴X¹, wherein X¹ is a direct bond, O, NR⁵, C₁₋₃alkyl,        C₂₋₄alkanoyl, CONR⁶R⁷, SO₂NR⁸R⁹ or SO₂R¹⁰ (wherein R⁵, R⁶ and R⁸        each independently represent hydrogen or C₁₋₂alkyl and R⁷, R⁹        and R¹⁰ each independently represent C₁₋₄alkyl and wherein R⁴ is        linked to R⁷, R⁹ or R¹⁰); and    -   R⁴ is phenyl or a 5 or 6 membered heterocyclic group with one or        two heteroatoms, selected independently from O, S and N, which        heterocyclic group may be saturated or unsaturated and which        phenyl or heterocyclic group may be substituted with one or two        substituents selected independently from oxo, hydroxy, halogeno,        C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy, trifluoromethyl, cyano,        amino, nitro and C₁₋₄alkoxycarbonyl;    -   2) X²C₂₋₄alkylX³C₁₋₃alkyl (wherein X² is O or NR¹¹ (wherein R¹¹        is hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and X³ is O,        NR¹², S, SO or SO₂ (wherein R¹² is hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl));    -   3) C₁₋₂alkylX⁴C₂₋₃alkylX⁵C₁₋₃alkyl (wherein X⁴ and X⁵ each        independently represent O, S, SO, SO₂ or NR¹³ (wherein R¹³ is        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); and    -   4) C₁₋₃alkylX⁶C₁₋₃alkyl (wherein X⁶ is O, S, SO, SO₂ or NR¹⁴        (wherein R¹⁴ is hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   R³ is hydroxy, halogeno, nitro, fluoromethyl, difluoromethyl,    trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,    C₁₋₃alkyl, cyano, amino or R¹⁵X⁷,    -   wherein X⁷ is a direct bond, O, CH₂, S, SO, SO₂, NR¹⁶CO, CONR¹⁷,        SO₂NR¹⁸, NR¹⁹SO₂ or NR²⁰ (wherein R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰        each independently represent hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl); and    -   R¹⁵ is selected from one of the following groups:    -   1) hydrogen or C₁₋₅alkyl, which may be substituted with one or        more groups selected independently from hydroxy, fluoro and        amino;    -   2) C₁₋₅alkylX⁸COR²¹ (wherein X⁸ is O or NR²² (wherein R²² is        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is        C₁₋₃alkyl, NR²³R²⁴ or OR²⁵ (wherein R²³, R²⁴ and R²⁵ each        independently represent hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl));    -   3) C₁₋₅alkylX⁹R²⁶ (wherein X⁹ is O, S, SO, SO₂, OCO, NR²⁷CO,        CONR²⁸, SO₂NR²⁹, NR³⁰SO₂ or NR³¹ (wherein R²⁷, R²⁸, R²⁹, R³⁰ and        R³¹ each independently represent hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁶ is hydrogen, C₁₋₃alkyl,        cyclopentyl, cyclohexyl or a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which C₁₋₃alkyl group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno and C₁₋₄alkoxy and which        heterocyclic group may be substituted with one or two        substituents selected independently from oxo, hydroxy, halogeno,        C₁₋₄alkyl,    -   C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);    -   4) C₁₋₅alkylX¹⁰C₁₋₅alkylX¹¹R³² (wherein X¹⁰ and X¹¹ each        independently represent O, S, SO, SO₂, NR³³CO, CONR³⁴, SO₂NR³⁵,        NR³⁶SO₂ or NR³⁷ (wherein R³³, R³⁴, R³⁵, R³⁶ and R³⁷ each        independently represent hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³² is hydrogen or C₁₋₃alkyl);    -   5) R³⁸ (wherein R³⁸ is a 5 or 6 membered saturated heterocyclic        group with one or two heteroatoms selected independently from O,        S and N, which heterocyclic group may be substituted with one or        two substituents selected independently from oxo, hydroxy,        halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);    -   6) C₁₋₅alkylR³⁸ (wherein R³⁸ is as defined hereinbefore),    -   7) C₂₋₅alkenylR³⁸ (wherein R³⁸ is as defined hereinbefore);    -   8) C₂₋₅alkenylR³⁸ (wherein R³⁸ is as defined hereinbefore);    -   9) R³⁹ (wherein R³⁹ is a pyridone group, a phenyl group or a 5        or 6 membered aromatic heterocyclic group with 1 to 3        heteroatoms selected independently from O, N and S, which        pyridone, phenyl or heterocyclic group may carry up to 5        substituents selected independently from hydroxy halogeno,        amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,        C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl,        cyano, CONR⁴⁰R⁴¹ and NR⁴²COR⁴³ (wherein R⁴⁰, R⁴¹, R⁴² and R⁴³        each independently represent hydrogen, C₁₋₄alkyl or        C₁₋₃alkoxyC₂₋₃alkyl));    -   10) C₁₋₅alkylR³⁹ (wherein R³⁹ is as defined hereinbefore);    -   11) C₂₋₅alkenylR³⁹ (wherein R³⁹ is as defined hereinbefore);    -   12) C₂₋₅alkynylR³⁹ (wherein R³⁹ is as defined hereinbefore);    -   13) C₁₋₅alkylX¹²R³⁹ (wherein X¹² is O, S, SO, SO₂, NR⁴⁴CO,        CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ and        R⁴⁸ each independently represent hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁹ is as defined hereinbefore);    -   14) C₂₋₅alkenylX¹³R³⁹ (wherein X¹³ is O, S, SO, SO₂, NR⁴⁹CO,        CONR⁵⁰, SO₂NR⁵¹, NR⁵²SO₂ or NR⁵³ (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and        R⁵³ each independently represent hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁹ is as defined hereinbefore);    -   15) C₂₋₅alkynylX¹⁴R³⁹ (wherein X¹⁴ is O, S, SO, SO₂, NR⁵⁴CO,        CONR⁵⁵, SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ and        R⁵⁸ each independently represent hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁹ is as defined hereinbefore);    -   16) C₁₋₃alkylX¹⁵C₁₋₃alkylR³⁹ (wherein X¹⁵ is O, S, SO, SO₂,        NR⁵⁹CO, CONR⁶⁰, SO₂NR⁶¹, NR⁶²SO₂ or NR⁶ (wherein R⁵⁹, R⁶⁰, R⁶¹,        R⁶² and R⁶³ each independently represent hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁹ is as defined hereinbefore); and    -   17) C₁₋₃alkylX¹⁵C₁₋₃alkylR³⁸ (wherein X¹⁵ and R³⁸ are as defined        hereinbefore);-   n is 0, 1, 2 or 3 when Z is a 6 membered heterocyclic ring and n is    0, 1 or 2 when Z is a membered heterocyclic ring;-   m is 0, 1, 2, 3 or 4;    as a free base or pharmaceutically acceptable salts thereof.

According to one aspect of the present invention compounds of formula Imay be used,

-   wherein R¹, R², R³, m and n are as defined hereinbefore; and-   ring Z is a 6 membered heterocyclic ring containing 1 or 2 nitrogen    atoms.

In another aspect of the invention compounds of formula I may be used,wherein Z is a 6 membered heterocyclic ring containing 1 or 2 nitrogenatoms and R¹ is hydrogen.

In a further aspect of the invention compounds of formula I may be used,wherein R² is halogeno, C₁₋₃alkyl, trifluoromethyl, cyano, carbamoyl,N—C₁₋₄alkylcarbamoyl, aminosulphonyl or a group R⁴X¹,

-   -   wherein X¹ is CONR⁶R⁷ (wherein R⁶ is hydrogen or C₁₋₂alkyl and        R⁷ is C₁₋₄alkyl and    -   wherein R⁴ is linked to R⁷); and        n is 0 or 1.

In yet another aspect of the invention compounds of formula I may beused, wherein R³ is R¹⁵X⁷,

-   -   wherein X⁷ is O; and    -   R¹⁵ is selected from one of the following groups:    -   1) hydrogen or C₁₋₅alkyl;    -   3) C₁₋₅alkylX⁹R²⁶ (wherein X⁹ is O (wherein R²⁶ is hydrogen or        C₁₋₃alkyl));    -   4) C₁₋₅alkylX¹⁰C₁₋₅alkylX¹¹R³² (wherein X¹⁰ and X¹¹ are O, and        R³² is hydrogen or C₁₋₃alkyl);    -   6) C₁₋₅alkylR³⁸ (wherein R³⁸ is a 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which heterocyclic group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and        C₁₋₄alkoxy);    -   7) C₂₋₅alkenylR³⁸ (wherein R³⁸ is as defined hereinbefore);    -   10) C₁₋₅alkylR³⁹ (wherein R³⁹ is a 5 or 6 membered aromatic        heterocyclic group with 1 to 3 heteroatoms selected        independently from O, N and S, which heterocyclic group may        carry up to 4 substituents selected independently from hydroxy        halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        trifluoromethyl, cyano, CONR⁴⁰R⁴¹ and NR⁴²COR⁴³ (wherein R⁴⁰,        R⁴¹R⁴² and R⁴³ each independently represent hydrogen, C₁₋₄alkyl        or C₁₋₃alkoxyC₂₋₃alkyl));    -   13) C₁₋₅alkylX¹²R³⁹ (wherein X¹² is O and R³⁹ is as defined        hereinbefore);        m is 0, 1 or 2.

One aspect of the invention relates to the use of compounds of formulaI, wherein R¹ is hydrogen, Z is a 6 membered heterocyclic ringcontaining 1 or 2 nitrogen atoms, R² is halogeno or C₁₋₃alkyl and n is 0or 1, R³ is morpholinopropoxy, dioxothiomorpholino-propoxy,morpholinobutenyl-oxy, pyridyloxy-ethoxy, triazolyl-ethoxy,imidazolyl-ethoxy, methoxy, methoxyethoxy or methoxyethoxy-ethoxy and mis 0, 1, or 2.

In another aspect of the invention, use is made of the followingcompounds in the manufacturing of a medicament for the treatment and/orprevention of conditions associated with glycogen synthase kinase-3;

-   4-(7-Azaoxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline,-   4-(7-Azaoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,-   4-(7-Azaoxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline,-   4-(5,7-Diaza-6-methyloxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,-   4-(7-Aza-6-chlorooxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,-   4-(5,7-Diaza-6-methyloxindol-3-yl)-6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline,-   4-(5,7-Diaza-6-methyloxidol-3-yl)-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,-   4-(7-Azaoxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,-   4-(7-Azaoxindol-3-yl)-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,-   4-(7-Azaoxindol-3-yl)-7-(4-morpholinobut-2-en-1-yloxy)quinazoline,-   4-(5,7-Diaza-6-methyloxindol-3-yl)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline,-   4-(7-Aza-6-chlorooxindol-3-yl)-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,    and-   4-(5,7-Diaza-6-methyloxindol-3-yl)-7-(3-(1,1-dioxothiomorpholino)-propoxy)quinazoline;    as a free base or pharmaceutically acceptable salts thereof.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’ the said group encompasses the first occurring andbroadest definition as well as each and all of the preferred definitionsof that group.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₅’ means a carbon group having 1, 2, 3, 4 or 5 carbonatoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups. C₁₋₅alkyl may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl.

The term “alkoxy” as used herein, unless stated otherwise includes“alkyl” O groups in which “alkyl” is as hereinbefore defined. C₁₋₅alkoxymay be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy,neo-pentyloxy.

The term “alkanoyl” as used herein, unless otherwise stated includesformyl and alkylC═O groups in which “alkyl” is as defined hereinbefore,for example C₂alkanoyl is ethanoyl and refers to CH₃C═O, C₁alkanoyl isformyl and refers to CHO.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl groups but referencesto individual alkenyl groups such as 2-butenyl are specific for thestraight chain version only. Unless otherwise stated, the term “alkenyl”advantageously refers to chains with 2 to 5 carbon atoms, preferably 3to 4 carbon atoms.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl groups but referencesto individual alkynyl groups such as 2-butynyl are specific for thestraight chain version only. Unless otherwise stated, the term “alkynyl”advantageously refers to chains with 2 to carbon atoms, preferably 3 to4 carbon atoms.

In this specification, unless stated otherwise, the term “5 or 6membered heterocyclic group with one or two heteroatoms, selectedindependently from O, S and N, which heterocyclic group may be saturatedor unsaturated” or “5 or 6 membered heterocyclic ring containing 1 to 3heteroatoms selected independently from O, N and S, which heterocyclicgroup may be saturated or unsaturated”, includes both heteroaromaticrings and heterocyclic rings that are saturated. Examples of suchheterocyclic groups includes, but are not limited to furyl, imidazolyl,isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolidinyl,imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranylor thiomorpholinyl.

In this specification, unless stated otherwise, the term “5 or 6membered saturated heterocyclic group with one or two heteroatoms,selected independently from O, S and N” may be, but are not limited toimidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl,piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl or thiomorpholinyl.

In this specification, unless stated otherwise, the term “5 or 6membered aromatic heterocyclic group with 1 to 3 heteroatoms, selectedindependently from O, N and S” may be, but are not limited to furyl,imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, triazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl orthienyl.

In this specification, unless stated otherwise, the term “5 or 6membered heterocyclic ring containing 1 to 3 heteroatoms selectedindependently from O, N and S” may be, but are not limited to furyl,imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyi.

In this specification, unless stated otherwise, the term halogeno may befluor, chlorine, bromine or iodine.

For the avoidance of any doubt, it is to be understood that when X⁷ is,for example, a group of formula NR¹⁶CO, it is the nitrogen atom besubstituted withing the R¹⁶ group which is attached to the quinazolinering and the carbonyl (CO) group is attached to R¹⁵, whereas when X⁷ is,for example, a group of formula CONR¹⁷, it is the carbonyl group whichis attached to the quinazoline ring and the nitrogen atom be substitutedwithing the R¹⁷ group is attached to R¹⁵. A similar convention appliesto the other two atoms X⁷ linking groups such as NR¹⁹SO₂ and SO₂NR¹⁸.When X⁷ is NR²⁰ it is the nitrogen atom be substituted withing the R²⁰group, which is linked to the quinazoline ring and to R¹⁵. An analogousconvention applies to other groups. It is further to be understood thatwhen X⁷ represents NR²⁰ and R²⁰ is C₁₋₃alkoxyC₂₋₃alkyl it is theC₂₋₃alkyl moiety, which is linked to the nitrogen atom of X⁷ and ananalogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that in acompound of formula I when R¹⁵ is, for example, a group of formulaC₁₋₅alkylX¹⁵C₁₋₅alkylR³⁹, it is the terminal C₁₋₅alkyl moiety, which islinked to X¹⁵, similarly when R¹⁵ is, for example, a group of formulaC₂₋₅alkenylR³⁹ it is the C₂₋₅alkenyl moiety, which is linked to X⁷ andan analogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that when R³⁹carries a C₁₋₄aminoalkyl substituent it is the C₁₋₄alkyl moiety, whichis attached to R³⁹ whereas when R³⁹ carries a C₁₋₄alkylamino substituentit is the amino moiety, which is attached to R³⁹ and an analogousconvention applies to other groups.

For the avoidance of any doubt when X¹ is C₂₋₄alkanoyl it is thecarbonyl moiety, which is linked to the heteroaromatic oxindole groupand it is the alkyl moiety, which is linked to R⁴ and an analogousconvention applies to other groups.

For the avoidance of any doubt when R² is a group X²C₂₋₄alkylX³C₁₋₃alkylit is X², which is linked to the heteroaromatic oxindole group and ananalogous convention applies to other groups. When R² is a groupC₁₋₂alkylX⁴C₂₋₃alkylX⁵C₁₋₃alkyl it is the C₁₋₂alkyl moiety, which islinked to the heteroaromatic oxindole group and an analogous conventionapplies to other groups.

Some compounds of formula I may have chiral centres and/or geometricisomeric centres (E- and Z-isomers), and it is to be understood that theinvention encompasses all such optical, diastereoisomers and geometricisomers that possess GSK3 inhibitory activity.

It is to be understood that the present invention also relates to anyand all tautomeric forms of the compounds of formula I.

The present invention relates to the use of compounds of formula I ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula I.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable acid addition salts of the compounds of thisinvention. In addition, a suitable pharmaceutically acceptable salt ofthe compounds of the invention is an alkali metal salt, an alkalineearth metal salt or a salt with an organic base.

Compound of formula I, or salt thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes include, for example, those illustrated inEuropean Patent Applications Publication Nos. 0520722, 0566226, 0602851,0635498 and 0636608 and PCT application WO 99/10349.

Pharmaceutical Composition

According to one aspect of the present invention there is provided apharmaceutical composition comprising a compound of formula I, as a freebase or salts thereof, for use in prevention and/or treatment ofdementia related diseases, Alzheimer's Disease and conditions associatedwith glycogen synthase kinase-3 and other conditions listed below.

The composition may be in a form suitable for oral administration, forexample as a tablet, pill, syrup, powder, granule or capsule, forparenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion) as a sterile solution,suspension or emulsion, for topical administration as an ointment, patchor cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using pharmaceutically acceptable carriers or diluents.

Suitable daily doses of the compounds of formula I in the treatment of amammal, including man, are approximately 0.01 to 250 mg/kg bodyweight atperoral administration and about 0.001 to 250 mg/kg bodyweight atparenteral administration. The typical daily dose of the activeingredients varies within a wide range and will depend on variousfactors such as the relevant indication, the route of administration,the age, weight and sex of the patient and may be determined by aphysician.

Illustrate representative pharmaceutical dosage forms containing acompound of formula I, as a free base or salts thereof, are described inWO 99/10349.

Medical Use

Surprisingly, it has been found that the compounds defined in thepresent invention, as a free base or salts thereof, are useful intherapy. The compounds of the present invention are well suited forinhibiting glycogen synthase kinase-3 (GSK3). Accordingly, the compoundsof the present invention are expected to be useful in the preventionand/or treatment of conditions associated with glycogen synthasekinase-3 activity, i.e. the compounds may be used to produce aninhibitory effect of GSK3 in mammals, including man, in need of suchprevention and/or treatment.

GSK3 is highly expressed in the central and peripheral nervous systemand in other tissues. Thus, it is expected that compounds of theinvention are well suited for the prevention and/or treatment ofconditions associated with glycogen synthase kinase-3 in the central andperipheral nervous system. In particular, the compounds of the inventionare expected to be suitable in the manufacture of a medicament for theprevention and/or treatment of dementia related diseases and Alzheimer'sDisease.

The dementia related diseases are selected from the group consisting ofFrontotemporal dementia Parkinson's Type, Parkinson dementia complex ofGuam, HIV dementia, diseases with associated neurofibrillar tanglepathologies, predemented states, vascular dementia, dementia with Lewybodies, Frontotemporal dementia and dementia pugilistica. The compoundsof the invention are also expected to be suitable in the manufacture ofa medicament for the prevention and/or treatment of amyotrophic lateralsclerosis, corticobasal degeneration, Down syndrome, Huntington'sDisease, Parkinson's Disease, postencephelatic parkinsonism, progressivesupranuclear palsy, Pick's Disease, Niemann-Pick's Disease, stroke, headtrauma and other chronic neurodegenerative diseases, Bipolar Disease,affective disorders, depression, schizophrenia, cognitive disorders,hair loss and contraceptive medication.

The compounds of the invention are further expected to be suitable inthe manufacture of a medicament for the prevention and/or treatment ofMild Cognitive Impairment, Age-Associated Memory Impairment, Age-RelatedCognitive Decline, Cognitive Impairement No Dementia, mild cognitivedecline, mild neurocognitive decline, Late-Life Forgetfulness, memoryimpairment and cognitive impairment and androgenetic alopecia.

The present invention relates also to the use of a compound of formula Ias defined hereinbefore, in the manufacture of a medicament for theprevention and/or treatment of conditions associated with glycogensynthase kinase-3.

The invention also provides for a method of prevention and/or treatmentof dementia related diseases, Alzheimer's Disease and conditionsassociated with glycogen synthase kinase-3 and other conditions listedabove comprising administrering to a mammal, including man, in need ofsuch prevention and/or treatment a therapeutically effective amount of acompound of formula I, as hereinbefore defined.

In the context of the present specification, the term “therapy” alsoincludes “prevention” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Non-Medical Use

In addition to their use in therapeutic medicine, the compounds offormula I as a free base or salts thereof, are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof GSK3 related activity in laboratory animals such as cats, dogs,rabbits, monkeys, rats and mice, as part of the search for newtherapeutics agents.

Pharmacology

Determination of ATP Competition in Scintillation Proximity GSK3β Assay.

GSK3β Scintillation Proximity Assay.

The competition experiments were carried out in duplicate with 10different concentrations of the inhibitors in clear-bottom microtiterplates (Wallac, Finland). A biotinylated peptide substrate,Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO₃H₂)-Pro-Gln-Leu(AstraZeneca, Lund), was added at a final concentration of 1 μM in anassay buffer containing 1 mU recombinant human GSK3β (Dundee University,UK), 12 mM morpholinepropanesulfonic acid (MOPS), pH 7.0, 0.3 mM EDTA,0.01% β-mercaptorethanol, 0.004% Brij 35 (a natural detergent), 0.5%glycerol and 0.5 μg BSA/25 μl. The reaction was initiated by theaddition of 0.04 Ci [γ-³³P]ATP (Amersham, UK) and unlabelled ATP at afinal concentration of 1 μM and assay volume of 25 μl. After incubationfor 20 minutes at room temperature, each reaction was terminated by theaddition of 25 μl stop solution containing 5 mM EDTA, 50 μM ATP, 0.1%Triton X-100 and 0.25 mg streptavidin coated Scintillation ProximityAssay (SPA) beads (Amersham, UK). After 6 hours the radioactivity wasdetermined in a liquid scintillation counter (1450 MicroBeta Trilux,Wallac). The inhibition curves were analysed by non-linear regressionusing GraphPad Prism, USA. The K_(m) value of ATP for GSK3β, used tocalculate the inhibition constants (K_(i)) of the various compounds, was20 μM.

The following abbreviations have been used:

-   ATP Adenosine Triphophatase-   BSA Bovin Serum Albumin-   EDTA Ethylenediaminetetraacetic acid-   GSK3 Glycogen synthase kinase 3-   MOPS Morpholinepropanesulfonic acid-   SPA Scintillation Proximity Assay.    Results

Typical K_(i) values for the compounds of the present invention are inthe range of about 0.001 to about 10,000 nM. Other values for K_(i) arein the range of about 0.001 to about 1000 nM. Further values for K_(i)are in the range of about 0.001 nM to about 300 nM.

1. A method for the treatment and/or prevention of conditions associatedwith glycogen synthase kinase-3 which comprises administering to apatient in need of such treatment and/or prevention a therapeuticallyeffective amount of a compound of formula I,

wherein the compound of formula I is a free base or pharmaceuticallyacceptable salt thereof; wherein: ring Z is a 5 or 6 memberedheterocyclic ring containing 1 to 3 heteroatoms selected independentlyfrom O, N and S but not more than 2 nitrogen atoms; R¹ is hydrogen orC₁₋₃alkyl; R² is hydroxy, halogeno, fluoromethyl, difluoromethyl,trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethyl, cyano, amino, nitro, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkanoyloxy, C₂₋₄alkanoyl, C₁₋₄alkanoylamino, C₁₋₄alkoxycarbonyl,C₁₋₄alkylthio, C₁₋₄alkylsulphinyl, C₁₋₄alkylsulphonyl, carbamoyl,N—C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,N—C₁₋₄alkylaminosulphonyl, N,N-di(C₁₋₄alkyl)aminosulphonyl orC₁₋₄alkylsulphonylamino, or R² is selected from one of the followinggroups: 1) R⁴X¹, wherein X¹ is a direct bond, O, NR⁵, C₁₋₃alkyl,C₂₋₄alkanoyl, CONR⁶R⁷, SO₂NR⁸R⁹ or SO₂R¹⁰ (wherein R⁵, R⁶ and R⁸ eachindependently represent hydrogen or C₁₋₂alkyl and R⁷, R⁹ and R¹⁰ eachindependently represent C₁₋₄alkyl and wherein R⁴ is linked to R⁷, R⁹ orR¹⁰); and R⁴ is phenyl or a 5 or 6 membered heterocyclic group with oneor two heteroatoms, selected independently from O, S and N, whichheterocyclic group may be saturated or unsaturated and which phenyl orheterocyclic group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno, C₁₋₃alkyl,C₁₋₃alkoxy, C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino, nitro andC₁₋₄alkoxycarbonyl; 2) X²C₂₋₄alkylX³C₁₋₃alkyl (wherein X² is O or NR¹¹(wherein R¹¹ is hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and X³ is O,NR¹², S, SO or SO₂ (wherein R¹² is hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₂alkylX⁴C₂₋₃alkylX⁵C₁₋₃alkyl (wherein X⁴and X⁵ each independently represent O, S, SO, SO₂ or NR¹³ (wherein R¹³is hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); and 4)C₁₋₃alkylX⁶C₁₋₃alkyl (wherein X⁶ is O, S, SO, SO₂ or NR¹⁴ (wherein R¹⁴is hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); R³ is hydroxy,halogeno, nitro, fluoromethyl, difluoromethyl, trifluoromethyl,fluoromethoxy, difluoromethoxy, trifluoromethoxy, C₁₋₃alkyl, cyano,amino or R¹⁵X⁷, wherein X⁷ is a direct bond, O, CH₂, S, SO, SO₂, NR¹⁶CO,CONR¹⁷, SO₂NR¹⁸, NR¹⁹SO₂ or NR²⁰ (wherein R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰each independently represent hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl); and R¹⁵ is selected from one of the followinggroups: 1) hydrogen or C₁₋₅alkyl, which may be substituted with one ormore groups selected independently from hydroxy, fluoro and amino; 2)C₁₋₅alkylX⁸COR²¹ (wherein X⁸ is O or NR²² (wherein R²² is hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is C₁₋₃alkyl, NR²³R²⁴ or OR²⁵(wherein R²³, R²⁴ and R²⁵ each independently represent hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3) C₁₋₅alkylX⁹R²⁶ (wherein X⁹ is O,S, SO, SO₂, OCO, NR²⁷CO, CONR²⁸, SO₂NR²⁹, NR³⁰ SO₂ or NR³¹ (wherein R²⁷,R²⁸, R²⁹, R³⁰ and R³¹ each independently represent hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R²⁶ is hydrogen, C₁₋₃alkyl, cyclopentyl,cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one ortwo heteroatoms selected independently from O, S and N, which C₁₋₃alkylgroup may be substituted with one or two substituents selectedindependently from oxo, hydroxy, halogeno and C₁₋₄alkoxy and whichheterocyclic group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4) C₁₋₅alkylX¹⁰C₁₋₅alkylX¹¹R³²(wherein X¹⁰ and X¹¹ each independently represent O, S, SO, SO₂, NR³³CO,CONR³⁴, SO₂NR³⁵, NR³⁶SO₂ or NR³⁷ (wherein R³³, R³⁴, R³⁵, R³⁶ and R³⁷each independently represent hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and R³² is hydrogen or C₁₋₃alkyl); 5) R³⁸ (wherein R³⁸ is a 5 or 6membered saturated heterocyclic group with one or two heteroatomsselected independently from O, S and N, which heterocyclic group may besubstituted with one or two substituents selected independently fromoxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 6)C₁₋₅alkylR³⁸ (wherein R³⁸ is as defined hereinbefore); 7) C₂₋₅alkenylR³⁸(wherein R³⁸ is as defined hereinbefore); 8) C₂₋₅alkynylR³⁸ (wherein R³⁸is as defined hereinbefore); 9) R³⁹ (wherein R³⁹ is a pyridone group, aphenyl group or a 5 or 6 membered aromatic heterocyclic group with 1 to3 heteroatoms selected independently from O, N and S, which pyridone,phenyl or heterocyclic group may carry up to 5 substituents selectedindependently from hydroxy halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy,carboxy, trifluoromethyl, cyano, CONR⁴⁰R⁴¹ and NR⁴² COR⁴³ (wherein R⁴⁰,R⁴¹, R⁴² and R⁴³ each independently represent hydrogen, C₁₋₄alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); 10) C₁₋₅alkylR³⁹ (wherein R³⁹ is as definedhereinbefore); 11) C₂₋₅alkenylR³⁹ (wherein R³⁹ is as definedhereinbefore); 12) C₂₋₅alkynylR³⁹ (wherein R³⁹ is as definedhereinbefore); 13) C₁₋₅alkylX¹²R³⁹ (wherein X¹² is O, S, SO, SO₂,NR⁴⁴CO, CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ andR⁴⁸ each independently represent hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³⁹ is as defined hereinbefore); 14)C₂₋₅alkenylX¹³R³⁹ (wherein X¹³ is O, S, SO, SO₂, NR⁴⁹CO, CONR⁵⁰,SO₂NR⁵¹, NR⁵² SO₂ or NR⁵³ (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ eachindependently represent hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁹ is as defined hereinbefore); 15) C₂₋₅alkynylX¹⁴R³⁹ (wherein X¹⁴ isO, S, SO, SO₂, NR⁵⁴CO, CONR⁵⁵, SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴,R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ each independently represent hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³⁹ is as defined hereinbefore); 16)C₁₋₃alkylX¹⁵C₁₋₃alkylR³⁹ (wherein X¹⁵ is O, S, SO, SO₂, NR⁵⁹ CO, CONR⁶⁰,SO₂NR⁶¹, NR⁶² SO₂ or NR⁶ (wherein R⁵⁹, R⁶⁰, R⁶¹, R⁶² and R⁶³ eachindependently represent hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR³⁹ is as defined hereinbefore); and 17) C₁₋₃alkylX¹⁵C₁₋₃alkylR³⁸(wherein X¹⁵ and R³⁸ are as defined hereinbefore); n is 0, 1, 2 or 3when Z is a 6 membered heterocyclic ring and n is 0, 1 or 2 when Z is a5 membered heterocyclic ring; m is 0, 1, 2, 3 or
 4. 2. The methodaccording to claim 1, wherein Z is a 6 membered heterocyclic ringcontaining 1 or 2 nitrogen atoms and R¹ is hydrogen.
 3. The methodaccording to claim 1, wherein R² is halogeno, C₁₋₃alkyl,trifluoromethyl, cyano, carbamoyl, N—C₁₋₄alkylcarbamoyl, aminosulphonylor a group R⁴X¹, wherein X¹ is CONR⁶R⁷ (wherein R⁶ is hydrogen orC₁₋₂alkyl and R⁷ is C₁₋₄alkyl and wherein R⁴ is linked to R⁷); and n is0 or
 1. 4. The method according to claim 1, wherein R³ is R¹⁵X⁷, whereinX⁷ is O; and R¹⁵ is selected from one of the following groups: 1)hydrogen or C₁₋₅alkyl; 3) C₁₋₅alkylX⁹R²⁶ (wherein X⁹ is O (wherein R²⁶is hydrogen or C₁₋₃alkyl)); 4) C₁₋₅alkylX¹⁰C₁₋₅alkylX¹¹R³² (wherein X¹⁰and X¹¹ are O, and R³² is hydrogen or C₁₋₃alkyl); 6) C₁₋₅alkylR³⁸(wherein R³⁸ is a 6 membered saturated heterocyclic group with one ortwo heteroatoms selected independently from O, S and N, whichheterocyclic group may be substituted with one or two substituentsselected independently from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 7) C₂₋₅alkenylR³⁸ (wherein R³⁸ is asdefined hereinbefore); 10) C₁₋₅alkylR³⁹ (wherein R³⁹ is a 5 or 6membered aromatic heterocyclic group with 1 to 3 heteroatoms selectedindependently from O, N and S, which heterocyclic group may carry up to4 substituents selected independently from hydroxy halogeno, amino,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, cyano, CONR⁴⁰R⁴¹ andNR⁴²COR⁴³ (wherein R⁴⁰, R⁴¹, R⁴² and R⁴³ each independently representhydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 13) C₁₋₅alkylX¹²R³⁹(wherein X¹² is O and R³⁹ is as defined hereinbefore); m is 0, 1 or 2.5. The method according to claim 1, wherein the compound is selectedfrom the group comprising of:4-(7-Azaoxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline,4-(7-Azaoxindol-3-yl)-6-methoxy-7-(morpholinopropoxy)quinazoline,4-(7-Azaoxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline,4-(5,7-Diaza-6-methyloxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,4-(7-Aza-6-chlorooxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,4-(5,7-Diaza-6-methyloxindol-3-yl)-6-methoxy-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinazoline,4-(5,7-Diaza-6-methyloxindol-3-yl)-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,4-(7-Azaoxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline,4-(7-Azaoxindol-3-yl)-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,4-(7-Azaoxindol-3-yl)-7-(4-morpholinobut-2-en-1-yloxy)quinazoline,4-(5,7-Diaza-6-methyloxindol-3-yl)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline,4-(7-Aza-6-chlorooxindol-3-yl)-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,and4-(5,7-Diaza-6-methyloxindol-3-yl)-7-(3-(1,1-dioxothiomorpholino)-propoxy)quinazoline;wherein the compound is a free base or pharmaceutically acceptable saltthereof.
 6. The method according to claim 1, wherein the treatmentand/or prevention of conditions associated with administering to apatient in need of such prevention and/or treatment comprises at leastone of the group consisting of dementia related diseases and Alzheimer'sDisease.
 7. The method for the prevention and/or treatment according toclaim 6, wherein the dementia related diseases are selected from thegroup consisting of Frontotemporal dementia Parkinson's Type, Parkinsondementia complex of Gaum, HIV dementia, diseases with associatedneurofibrillar tangle pathologies, predemented states, vasculardementia, dementia with Lewy bodies, Frontotemporal dementia anddementia pugilistica.
 8. (canceled)
 9. (canceled)
 10. A pharmaceuticalcomposition for use in prevention and/or treatment of dementia relateddiseases, Alzheimer's Disease and conditions associated with glycogensynthase kinase-3, comprising a therapeutically effective amount of acompound of formula I as defined in any one of claims 1 to 5 andpharmaceutically acceptable carriers or diluents.
 11. (canceled)
 12. Amethod of prevention and/or treatment of a medical condition selectedfrom the group consisting of amyotrophic lateral sclerosis, corticobasaldegeneration, Down syndrome, Huntington's Disease, Parkinson's Disease,postencephelatic parkinsonism, progressive supranuclear palsy, Pick'sDisease, Niemann-Pick's Disease, stroke, head trauma and other chronicneurodegenerative diseases, Bipolar Disease, affective disorders,depression, schizophrenia, cognitive disorders, hair loss andcontraceptive medication, the method comprising administering to amammal in need of such prevention and/or treatment, a therapeuticallyeffective amount of the compound of formula I as defined in claim
 1. 13.A method of prevention and/or treatment of a medical condition selectedfrom the group consisting of Mild Cognitive Impairment, Age-AssociatedMemory Impairment, Age-Related Cognitive Decline, Cognitive ImpairmentNo Dementia, mild cognitive decline, mild neurocognitive decline,Late-Life Forgetfulness, memory and cognitive impairment andandrogenetic alopecia, the method comprising administering to a mammalin need of such prevention and/or treatment, a therapeutically effectiveamount of the compound of formula I as defined in claim 1.